PROJECT SUMMARY Alzheimer?s disease (AD) is a devastating age-associated degenerative brain disease and the most common cause of dementia. By age 85, more than 30% of individuals will have AD. To date, there are no preventive measures or effective cures; hence novel treatment strategies are urgently needed. AD is characterized by memory decline, cognitive dysfunction, amyloid-beta (A?) deposition, neurofibrillary tangles and neuroinflammation [1]. However, anti-inflammatory treatments have been largely unsuccessful, prompting us to reassess the contribution of tissue-resident microglia to AD onset and progression. While some reports show that pro-inflammatory microglia are associated with disease progression [2], recent technological advances allowing single-cell analysis have identified protective disease-associated microglia (DAM) and their distinct phenotypic characteristics [3]. A feature of these protective DAMs is lipoprotein Lipase (LPL), the rate-limiting enzyme in the hydrolysis of triglyceride (TG)-rich lipoproteins. These findings add to a growing body of literature highlighting a protective role of LPL in AD pathophysiology. For example, single-nucleotide polymorphisms (SNPs) in the coding region of the LPL gene are associated with reduced enzyme activity and increased AD risk [4]. Recent studies suggest that glial-LPL facilitates phagocytic uptake and degradation of A? [5, 6], suggesting that LPL-mediated protection is due to enhanced A? clearance. In support, our lab has recently shown that LPL is a feature of reparative phagocytic microglia and is involved in lipid and lipoprotein clearance [7]. Importantly, our preliminary data show that the LPL activator, NO-1886, can elevate LPL abundance and activity in microglia. In addition, while microglial-LPL can facilitate uptake of ApoE (Isoforms 2 and 3) containing lipoproteins, both the hydrolytic and endocytotic function of LPL is inhibited by ApoE4. Taken together these findings have led to our central hypothesis, that enhancing microglial LPL abundance will facilitate endocytosis and clearance of A? and ApoE containing HDL-like lipoproteins in the CNS to ameliorate the progression of AD. To test this hypothesis, in AIM I. we will determine the feasibility of NO-1886 to modulate biochemical and behavioral features of AD in an established mouse model of AD (5XFAD); and in AIM II we will adopt a multisystem approach to determine the mechanism of microglial LPL-mediated A? and ApoE (2, 3 and 4) uptake. This R21 application brings together an interdisciplinary research team with vast expertise in lipid and lipoprotein biochemistry (Drs. Eckel and Bruce), and the cellular basis of AD pathogenesis (Dr. Potter) that are uniquely positioned to determine the role of LPL in AD, and to test the feasibility of the microglial LPL as a novel target for AD treatment. Findings from these studies will serve to develop an exciting new program of research that will quickly translate to treatments that will prevent, delay and/or reverse AD progression.